Stem cell (HSC) self-renewal and differentiation are central to the maintenance of normal hematopoiesis. We have performed an extensive analysis of individual, clonally derived HSC. The data showed that HSC behaviors are largely fixed on the level of the HSC. Consequently, the adult HSC compartment consists of subsets of HSC, each with preprogrammed self-renewal and differentiation capacity. We showed that the HSC compartment can be divided into 3 subsets, namely balanced, myeloid-biased, and lymphoid-biased HSC. These three types together make up the complete HSC compartment. HSC in all classes have self-renewal capacity although to different degrees. All HSCs contribute to all hematopoietic lineages, albeit with a noticeably different ratio of lymphoid and myeloid cells in blood. The lineage potential of all HSCs is a stable HSC-intrinsic feature that is inherited to daughter HSC through many rounds of self-renewal divisions. The discovery of these HSC classes now opens the unique opportunity to define the developmental and molecular mechanisms that control lineage potential and self-renewal capacity on the level of the HSC. We propose to define the onset of the adult-type fixed behavior during development, define whether epigenetic events contribute to the fixed lineage potential, test whether myeloid-bias predisposes HSC for myeloid Leukemia, and explore ways to prospectively isolate different types of HSC. Data from the proposed studies may provide better ways to treat leukopenia and may help in the design of approaches to selectively eradicate leukemic stem cells. PUBLIC HEALTH RELEVANCE Much effort is spent on trying to change blood forming stem cells to improve their performance for transplantation and therapeutic applications. We showed that the blood forming stem cells consists of distinct classes, each with fixed, predetermined behavior. This predicts that attempts to modulate the behavior of these stem cells will have limited success. Rather, different types of stem cells could be pre-selected to be optimal for each application. To find the right type of stem cell for each application, we need to better understand the molecular and developmental mechanisms that distinguish the different types of stem cells. [unreadable] [unreadable] [unreadable] [unreadable]